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Very Long-Chain Acyl-CoA Dehydrogenase Deficiency, Genetic Testing

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare inherited metabolic disorder that affects fatty acid oxidation. This disorder impairs the body's ability to convert certain fats into energy, particularly during fasting or increased energy demands. VLCAD is an enzyme crucial in breaking down very long-chain fatty acids for energy production. VLCADD is often included in neonatal screening programs, where acylcarnitine levels are usually determined. Its incidence is between 1 in 30.000 and 1 in 100.000 births.

Very long-chain acyl-CoA dehydrogenase genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Key features and aspects of Very Long-chain Acyl-CoA Dehydrogenase Deficiency include:

  • Genetic Basis: VLCAD deficiency is caused by ACADVL gene mutations, which provide instructions for producing the VLCAD enzyme. Inheritance is autosomal recessive, meaning an individual must inherit two copies of the mutated gene (one from each parent) to develop the disorder.
  • Fatty Acid Oxidation: The deficiency of VLCAD results in the impaired breakdown of very long-chain fatty acids. These fatty acids are a significant energy source, especially during fasting or increased energy demand (e.g., illness, exercise).
  • Clinical Presentation: Symptoms of VLCAD deficiency can vary and may include hypoglycemia (low blood sugar), muscle weakness, lethargy, failure to thrive, and cardiomyopathy (heart muscle disease). Symptoms often become apparent during infancy or early childhood.
  • Metabolic Crisis: Individuals with VLCAD deficiency are at risk of metabolic crises, especially during fasting or illnesses, when the body's energy demands increase. These crises can lead to severe symptoms, including hypoketotic hypoglycemia, which is characterized by low blood sugar without the expected buildup of ketones.
  • Cardiac Involvement: Cardiac complications, such as cardiomyopathy, can be a significant feature of VLCAD deficiency.
  • Diagnosis: Diagnosis typically involves biochemical testing to detect abnormalities in fatty acid oxidation, genetic testing to identify mutations in the ACADVL gene, and metabolic studies during periods of fasting.
  • Management: Treatment involves avoiding long periods of fasting and ensuring a constant intake of calories. A specific dietary regimen may be recommended to provide an alternative energy source, and supplements such as medium-chain triglycerides (MCTs) may be used.
  • Emergency Protocols: Families of individuals with VLCAD deficiency often receive guidance on managing metabolic crises, including emergency protocols for providing glucose during illness or fasting.

Early diagnosis and intervention are critical in managing VLCAD deficiency. Close collaboration between metabolic specialists, dietitians, and other healthcare professionals is essential to optimize care and prevent metabolic crises.

VLCAD deficiency is a clinically heterogeneous disease and is divided into three subtypes:

  • Severe infantile VLCADD manifests between 3 and 12 months of life and during the neonatal period. It is characterized by hypoketotic hypoglycemias, hepatopathies, cardiac arrhythmias, and cardiomyopathies that can be life-threatening.
  • Moderately severe infantile VLCADD has a later onset (early neonatal period to childhood) and usually presents with hypoketotic hypoglycemia, low mortality and, rarely, cardiomyopathy.
  • Late-onset myopathic VLCADD occurs in older children and young adults (usually more than 10 years of age), with isolated skeletal muscle involvement, physical exercise intolerance, myalgia, rhabdomyolysis, and rheumatoid arthritis. It is generally triggered by physical exercise, fasting, heat or cold, or stress, although viral infections may also provoke or accelerate the process.
More Information

The ACADVL gene encodes for the very long-chain acyl-CoA dehydrogenase protein or VLCAD ("Very Long-Chain acyl-CoA Dehydrogenase"), which is a protein involved in the metabolism of long-chain fatty acids.

Very long-chain acyl-CoA dehydrogenase is inherited as an autosomal recessive trait, although it can also occur in compound heterozygosis, i.e., when one is heterozygous for two pathogenic variants. The c.848T>C or p. Val283Ala variant is the most common pathogenic variant in VLCADD patients and accounts for approximately 10-29% of the disease-causing alleles. This variant has been observed in homozygosis and compound heterozygosis.

Very long-chain acyl-CoA dehydrogenase genetic testing analyzes the 20 most frequent pathogenic mutations of the ACADVL gene.

The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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